Brain development requires orchestrated formation of connections between nerve cells. These synaptic connections are the main units of communication in the brain, where chemical neurotransmitter signaling occurs. This proposal is on synaptic organizing proteins, genes that function as master regulators of synaptic development. Such proteins alone can trigger formation of nerve cell connections. In preliminary studies, from an unbiased screen we identified a new protein that triggers development of presynaptic connections in contacting nerve cell processes. It is one of a family of 3 highly related proteins. The proposed experiments will assess the ability of these 3 synaptic organizing proteins to drive formation of nerve cell connections of different neurotransmitter types, and will identify protein domains responsible. These novel synaptic organizing proteins can be cleared by extracellular proteolysis. Preliminary data suggests that cleavage abolishes synaptic organizing activity; thus we will study how cleavage is regulated. Finally, a major aim is to use a combination of mouse molecular genetics, fluorescence imaging, biochemistry, electrophysiology, and behavioral assays to determine the importance of these genes in brain development and synaptic function. This combined in vivo approach will allow an understanding of how these genes contribute to brain wiring, synaptic composition, structure, and function, and how changes in specific synapses result in behavioral changes. Such approaches often result in useful models for psychiatric disorders. The central hypothesis is that these genes are crucial for organizing synaptic development, for recruiting molecular components essential for proper synaptic structure and function in brain circuits important for cognition. Variation in one of these genes is linked to word recall ability, and lower organisms lacking the single homologous gene are deficient in learning. Furthermore, variants in the major synaptic organizing gene families studied to date, neuroligins and neurexins, predispose to autism spectrum disorders, schizophrenia, and mental retardation. Thus, in studying these synaptic organizing genes, we hope to increase our understanding of the molecular basis for cognitive disorders and to help design rational drug treatments. As triggers for building synaptic connections, these genes may also have implications for a number of neurological disorders from epilepsy and stroke to Alzheimer's and Parkinson's diseases. It may be possible to harness the ability of these genes to trigger formation of nerve cell connections to repair and regenerate the lost and injured connections in these debilitating disorders. PUBLIC HEALTH RELEVANCE: The goal is to understand how specific genes control the wiring and function of brain cells in health and disease. Variations in the gene under study influence word recall ability, and lower organisms lacking this gene are deficient in learning. The proposed research will reveal how this gene organizes connections between brain cells, controlling their partner choice, structure, biochemical composition and function to regulate behavior, and how alterations is such genes predispose to psychiatric disorders.